KDIGO 2012 anemia guideline english

Not Graded Investigation of anemia 1.3: In patients with CKD and anemia regardless of age and CKD stage, include the following tests in initial evaluation of the anemia Not Graded: K Com

VOLUME 2 | ISSUE 4 | AUGUST 2 2012

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OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF NEPHROLOGY

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease

KDIGO gratefully acknowledges the following consortium of sponsors that make our initiatives possible: Abbott, Amgen,Bayer Schering Pharma, Belo Foundation, Bristol-Myers Squibb, Chugai Pharmaceutical, Coca-Cola Company, Dole FoodCompany, Fresenius Medical Care, Genzyme, Hoffmann-LaRoche, JC Penney, Kyowa Hakko Kirin, NATCO—TheOrganization for Transplant Professionals, NKF-Board of Directors, Novartis, Pharmacosmos, PUMC Pharmaceutical,Robert and Jane Cizik Foundation, Shire, Takeda Pharmaceutical, Transwestern Commercial Services, Vifor Pharma,and Wyeth

Sponsorship Statement: KDIGO is supported by a consortium of sponsors and no funding is accepted for the development

of specific guidelines

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease

Tables and Figures v

KDIGO Board Members vi

Reference Keys vii

Abbreviations and Acronyms viii

Notice 279

Foreword 280

Work Group Membership 281

Abstract 282

Summary of Recommendation Statements 283

Chapter 1: Diagnosis and evaluation of anemia in CKD 288

Chapter 2: Use of iron to treat anemia in CKD 292

Chapter 3: Use of ESAs and other agents to treat anemia in CKD 299

Chapter 4: Red cell transfusion to treat anemia in CKD 311

Methods for Guideline Development 317

Biographic and Disclosure Information 324

Acknowledgments 330

References 331

& 2012 KDIGO

VOL 2 | ISSUE 4 | AUGUST (2) 2012

Table 4 Practical approach in presence of ESA hyporesponsiveness

Figure 1 Receiver operating characteristic (ROC) curves, examining the utility of iron status tests to distinguish iron

deficient from nondeficient study patients293

Figure 2 Sensitivity and specificity of TSAT and serum ferritin and their combination (TSAT + ferritin) and bone marrow

iron (BM iron) to identify correctly a positive erythropoietic response (Z1-g/dl [Z10-g/l] increase in Hb [DHb]) tointravenous iron in 100 nondialysis patients with CKD (areas under the ROCs)

294

Figure 3 Lymphocytotoxic antibody reactivity against random donor test panel in relation to the number of blood

transfusions313

Figure 4 Algorithms for red cell transfusion use in CKD patients

315

Additional information in the form of supplementary materials can be found online at http://www.kdigo.org/clinical_practice_guidelines/anemia.php

& 2012 KDIGO

KDIGO Board Members

Garabed Eknoyan, MDNorbert Lameire, MD, PhDFounding KDIGO Co-ChairsKai-Uwe Eckardt, MDImmediate Past Co-ChairBertram L Kasiske, MD

KDIGO Co-Chair

David C Wheeler, MD, FRCPKDIGO Co-Chair

Omar I Abboud, MD, FRCP

Sharon Adler, MD, FASN

Rajiv Agarwal, MD

Sharon P Andreoli, MD

Gavin J Becker, MD, FRACP

Fred Brown, MBA, FACHE

Pablo Massari, MDPeter A McCullough, MD, MPH, FACC, FACPRafique Moosa, MD

Miguel C Riella, MDAdibul Hasan Rizvi, MBBS, FRCPBernardo Rodriquez-Iturbe, MDRobert Schrier, MD

Justin Silver, MD, PhDMarcello Tonelli, MD, SM, FRCPCYusuke Tsukamoto, MD

Theodor Vogels, MSWAngela Yee-Moon Wang, MD, PhD, FRCPChristoph Wanner, MD

Elena Zakharova, MD, PhD

NKF-KDIGO GUIDELINE DEVELOPMENT STAFF

Kerry Willis, PhD, Senior Vice-President for Scientific Activities

Michael Cheung, MA, Guideline Development Director

Sean Slifer, BA, Guideline Development Manager

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& 2012 KDIGO

CONVERSION FACTORS OF METRIC UNITS TO SI UNITS

Parameter Metric units Conversion factor SI units

Grade Quality of evidence Meaning

A High We are confident that the true effect lies close to that of the estimate of the effect.

B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility

that it is substantially different.

C Low The true effect may be substantially different from the estimate of the effect.

D Very Low The estimate of effect is very uncertain, and often will be far from the truth.

CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO

CKD Categories Definition

CKD CKD of any stage (1–5), with or without a kidney transplant, including both non-dialysis

dependent CKD (CKD 1–5ND) and dialysis-dependent CKD (CKD 5D) CKD ND Non-dialysis-dependent CKD of any stage (1–5), with or without a kidney transplant

(i.e., CKD excluding CKD 5D) CKD T Non-dialysis-dependent CKD of any stage (1–5) with a kidney transplant

Level 1

‘We recommend’

Most people in your situation would want the recommended course of action and only a small proportion would not.

Most patients should receive the recommended course of action.

The recommendation can be evaluated

as a candidate for developing a policy or

but many would not.

Different choices will be appropriate for different patients Each patient needs help to arrive at a management decision consistent with her or his values and preferences.

The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.

*The additional category ‘Not Graded’ was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE RECOMMENDATIONSWithin each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or Not Graded, and the quality of thesupporting evidence is shown as A, B, C, or D

Reference Keys

CKD Stage Description GFR (ml/min per 1.73 m 2

)

1 Kidney damage with normal or increased GFR Z 90

2 Kidney damage with mild decreased GFR 60–89

Abbreviations and Acronyms

Evaluation

Renal Insufficiency

Prospective Cohort Study

Anemia Treatment With Epoetin Beta Trial

EuroQol GroupFACT-Fatigue Functional Assessment of Cancer

Therapy-Fatigue

Development, and Evaluation

body water volume

Short-Form Health Survey

with Aranesp Therapy

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Kidney International Supplements (2012) 2, 279; doi:10.1038/kisup.2012.37

SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINE

This Clinical Practice Guideline document is based upon systematic literature searches last

conducted in October 2010, supplemented with additional evidence through March 2012 It is

designed to provide information and assist decision making It is not intended to define a

standard of care, and should not be construed as one, nor should it be interpreted as prescribing

an exclusive course of management Variations in practice will inevitably and appropriately occur

when clinicians take into account the needs of individual patients, available resources, and

limitations unique to an institution or type of practice Every health-care professional making

use of these recommendations is responsible for evaluating the appropriateness of applying them

in any particular clinical situation The recommendations for research contained within this

document are general and do not imply a specific protocol

SECTION II: DISCLOSURE

Kidney Disease: Improving Global Outcomes (KDIGO) makes every effort to avoid any actual or

reasonably perceived conflicts of interest that may arise as a result of an outside relationship or a

personal, professional, or business interest of a member of the Work Group All members of the

Work Group are required to complete, sign, and submit a disclosure and attestation form

showing all such relationships that might be perceived or actual conflicts of interest This

document is updated annually and information is adjusted accordingly All reported information

will be printed in the final publication and are on file at the National Kidney Foundation (NKF),

Managing Agent for KDIGO

http://www.kidney-international.org

& 2012 KDIGO

Copyright & 2012 by KDIGO All rights reserved

Single photocopies may be made for personal use as allowed by national copyright laws

Special rates are available for educational institutions that wish to make photocopies fornon-profit educational use No part of this publication may be reproduced, amended, ortransmitted in any form or by any means, electronic or mechanical, including photocopying,recording, or any information storage and retrieval system, without explicit permission inwriting from KDIGO Details on how to seek permission for reproduction or translation,and further information about KDIGO’s permissions policies can be obtained by contactingAnita Viliusis, KDIGO Permissions Manager, at anita.viliusis@kidney.org

To the fullest extent of the law, neither KDIGO, Kidney International Supplements, NationalKidney Foundation (KDIGO Managing Agent) nor the authors, contributors, or editors,assume any liability for any injury and/or damage to persons or property as a matter ofproducts liability, negligence or otherwise, or from any use or operation of any methods,products, instructions, or ideas contained in the material herein

Kidney International Supplements (2012) 2, 280; doi:10.1038/kisup.2012.38

It is our hope that this document will serve several useful

purposes Our primary goal is to improve patient care We

hope to accomplish this, in the short term, by helping

clinicians know and better understand the evidence (or lack

of evidence) that determines current practice By providing

comprehensive evidence-based recommendations, this

guide-line will also help define areas where evidence is lacking and

research is needed Helping to define a research agenda is an

often neglected, but very important, function of clinical

practice guideline development

We used the Grading of Recommendations Assessment,

Development, and Evaluation (GRADE) system to rate the

strength of evidence and the strength of recommendations In

all, there were only 2 (5.4%) recommendations in this guideline

for which the overall quality of evidence was graded ‘A,’ whereas

9 (24.3%) were graded ‘B,’ 14 (37.8%) were graded ‘C,’ and 12

(32.4%) were graded ‘D.’ Although there are reasons other than

quality of evidence to make a grade 1 or 2 recommendation, in

general, there is a correlation between the quality of overall

evidence and the strength of the recommendation Thus, there

were 15 (40.5%) recommendations graded ‘1’ and 22 (59.5%)

graded ‘2.’ There were 2 (5.4%) recommendations graded ‘1A,’

8 (21.6%) were ‘1B,’ 1 (2.7%) were ‘1C,’ and 4 (10.8%) were

‘1D.’ There were 0 (0%) graded ‘2A,’ 1 (2.7%) were ‘2B,’ 13

(35.1%) were ‘2C,’ and 8 (21.6%) were ‘2D.’ There were 22

(37.3%) statements that were not graded

Some argue that recommendations should not be madewhen evidence is weak However, clinicians still need to makeclinical decisions in their daily practice, and they often ask,

‘What do the experts do in this setting?’ We opted to giveguidance, rather than remain silent These recommendationsare often rated with a low strength of recommendation and alow strength of evidence, or were not graded It is importantfor the users of this guideline to be cognizant of this (seeNotice) In every case these recommendations are meant to

be a place for clinicians to start, not stop, their inquiries intospecific management questions pertinent to the patients theysee in daily practice

We wish to thank the Work Group Co-Chairs,Drs John McMurray and Pat Parfrey, along with all of theWork Group members who volunteered countless hours

of their time developing this guideline We also thankthe Evidence Review Team members and staff of theNational Kidney Foundation who made this project possible.Finally, we owe a special debt of gratitude to the manyKDIGO Board members and individuals who volunteeredtime reviewing the guideline, and making very helpfulsuggestions

Bertram L Kasiske, MD David C Wheeler, MD, FRCPKDIGO Co-Chair KDIGO Co-Chair

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Work Group Membership

Kidney International Supplements (2012) 2, 281; doi:10.1038/kisup.2012.39

WORK GROUP CO-CHAIRSJohn J V McMurray, MD, FRCP, FESC

BHF Glasgow Cardiovascular Research Centre

Glasgow, United Kingdom

Patrick S Parfrey, MD, FRCPC, FRSCMemorial University Medical School

St John’s, Canada

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WORK GROUPJohn W Adamson, MD

University of California at San Diego

San Diego, CA, USA

Pedro Aljama, MD, PhD

Hospital Universitario Reina Sofı´a

Co´rdoba, Spain

Jeffrey S Berns, MD

The Perelman School of Medicine

at the University of Pennsylvania

Philadelphia, PA, USA

North Shore-LIJ Health System

Manhasset, NY, USA

Tomas Ganz, PhD, MD

David Geffen School of Medicine at UCLA

Los Angeles, CA, USA

Iain C Macdougall, BSc, MD, FRCPKing’s College Hospital

London, United KingdomRuth A McDonald, MDSeattle Children’s HospitalSeattle, WA, USALawrence P McMahon, MBBS, MDMonash University

Box Hill, AustraliaGregorio T Obrador, MD, MPHUniversidad Panamericana School of MedicineMexico City, Mexico

Giovanni FM Strippoli, MD, PhD, MPHConsorzio Mario Negri Sud

Chieti, ItalyGu¨nter Weiss, MDMedical University of InnsbruckInnsbruck, Austria

Andrzej Wie˛cek, MD, PhD, FRCPSilesian University School of MedicineKatowice, Poland

EVIDENCE REVIEW TEAM

Tufts Center for Kidney Disease Guideline Development and Implementation

Tufts Medical Center, Boston, MA, USA:

Ethan M Balk, MD, MPH; Project Director; Program Director, Evidence-based Medicine

Ashish Upadhyay, MD, Assistant Project DirectorDana C Miskulin, MD, MS, Staff NephrologistAmy Earley, BS, Project CoordinatorShana Haynes, MS, DHSc, Research AssistantJenny Lamont, MS, Project Manager

In addition, support and supervision were provided by:

Katrin Uhlig, MD, MS; Director, Guideline Development

Kidney International Supplements (2012) 2, 282; doi:10.1038/kisup.2012.40

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for

Anemia in Chronic Kidney Disease aims to provide guidance on diagnosis, evaluation,

management and treatment for all CKD patients (non-dialysis, dialysis, kidney transplant

recipients and children) at risk of or with anemia Guideline development followed an explicit

process of evidence review and appraisal The guideline contains chapters addressing diagnosis

and evaluation of anemia in CKD and the use of various therapeutic agents (iron, ESAs and

other agents) and red cell transfusion as means of treatment Treatment approaches are

addressed in each chapter and guideline recommendations are based on systematic reviews of

relevant trials Appraisal of the quality of the evidence and the strength of recommendations

followed the GRADE approach Ongoing areas of controversies and limitations of the evidence

are discussed and additional suggestions are also provided for future research

Keywords: anemia in CKD; blood transfusions; clinical practice guideline;

erythropoiesis-stimulating agent; KDIGO; evidence-based recommendation; iron; systematic review

http://www.kidney-international.org

& 2012 KDIGO

In citing this document, the following format should be used: Kidney Disease: Improving

Global Outcomes (KDIGO) Anemia Work Group KDIGO Clinical Practice Guideline for

Anemia in Chronic Kidney Disease Kidney inter., Suppl 2012; 2: 279–335

Summary of Recommendation Statements

Kidney International Supplements (2012) 2, 283–287; doi:10.1038/kisup.2012.41

Chapter 1: Diagnosis and evaluation of anemia in CKD

TESTING FOR ANEMIA

Frequency of testing for anemia

1.1.1: For CKD patients without anemia (as defined below in Recommendation 1.2.1 for adults and Recommendation1.2.2 for children), measure Hb concentration when clinically indicated and (Not Graded):

K at least annually in patients with CKD 3

K at least twice per year in patients with CKD 4–5ND

K at least every 3 months in patients with CKD 5HD and CKD 5PD

1.1.2: For CKD patients with anemia not being treated with an ESA, measure Hb concentration when clinically indicatedand (Not Graded):

K at least every 3 months in patients with CKD 3–5ND and CKD 5PD

K at least monthly in patients with CKD 5HD

[See Recommendations 3.12.1–3.12.3 for measurement of Hb concentration in patients being treated withESA.]

Diagnosis of anemia

1.2.1: Diagnose anemia in adults and children 415 years with CKD when the Hb concentration iso13.0 g/dl (o130 g/l)

in males ando12.0 g/dl (o120 g/l) in females (Not Graded)

1.2.2: Diagnose anemia in children with CKD if Hb concentration iso11.0 g/dl (o110 g/l) in children 0.5–5 years, o11.5g/dl (115 g/l) in children 5–12 years, ando12.0 g/dl (120 g/l) in children 12–15 years (Not Graded)

Investigation of anemia

1.3: In patients with CKD and anemia (regardless of age and CKD stage), include the following tests in initial evaluation

of the anemia (Not Graded):

K Complete blood count (CBC), which should include Hb concentration, red cell indices, white blood cell countand differential, and platelet count

K Absolute reticulocyte count

K Serum ferritin level

K Serum transferrin saturation (TSAT)

K Serum vitamin B12and folate levels

Chapter 2: Use of iron to treat anemia in CKD

TREATMENT WITH IRON AGENTS

2.1.1: When prescribing iron therapy, balance the potential benefits of avoiding or minimizing blood transfusions, ESAtherapy, and anemia-related symptoms against the risks of harm in individual patients (e.g., anaphylactoid andother acute reactions, unknown long-term risks) (Not Graded)

2.1.2: For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of IV iron (or in CKD NDpatients alternatively a 1–3 month trial of oral iron therapy) if (2C):

K an increase in Hb concentration without starting ESA treatment is desired* and

K TSAT isr30% and ferritin is r500 ng/ml (r500 mg/l)

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*Based on patient symptoms and overall clinical goals, including avoidance of transfusion, improvement in anemia-related symptoms, and after exclusion of active infection.

2.1.3: For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron(or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C):

K an increase in Hb concentration** or a decrease in ESA dose is desired*** and

K TSAT isr30% and ferritin is r500 ng/ml (r500 mg/l)

2.1.4: For CKD ND patients who require iron supplementation, select the route of iron administration based on theseverity of iron deficiency, availability of venous access, response to prior oral iron therapy, side effects with priororal or IV iron therapy, patient compliance, and cost (Not Graded)

2.1.5: Guide subsequent iron administration in CKD patients based on Hb responses to recent iron therapy,

as well as ongoing blood losses, iron status tests (TSAT and ferritin), Hb concentration, ESA responsivenessand ESA dose in ESA treated patients, trends in each parameter, and the patient’s clinical status.(Not Graded)

2.1.6: For all pediatric CKD patients with anemia not on iron or ESA therapy, we recommend oral iron (or IV iron inCKD HD patients) administration when TSAT isr20% and ferritin is r100 ng/ml (r100 lg/l) (1D)

2.1.7: For all pediatric CKD patients on ESA therapy who are not receiving iron supplementation, we recommend oraliron (or IV iron in CKD HD patients) administration to maintain TSAT 420% and ferritin 4100 ng/ml (4100 lg/l) (1D)

IRON STATUS EVALUATION

2.2.1: Evaluate iron status (TSAT and ferritin) at least every 3 months during ESA therapy, including the decision to start

or continue iron therapy (Not Graded)

2.2.2: Test iron status (TSAT and ferritin) more frequently when initiating or increasing ESA dose, when there is bloodloss, when monitoring response after a course of IV iron, and in other circumstances where iron stores may becomedepleted (Not Graded)

CAUTIONS REGARDING IRON THERAPY

2.3: When the initial dose of IV iron dextran is administered, we recommend (1B) and when the initial dose of IV dextran iron is administered, we suggest (2C) that patients be monitored for 60 minutes after the infusion, and thatresuscitative facilities (including medications) and personnel trained to evaluate and treat serious adverse reactions

non-be available

Iron during infection

2.4: Avoid administering IV iron to patients with active systemic infections (Not Graded)

Chapter 3: Use of ESAs and other agents to treat

**Consistent with Recommendations #3.4.2 and 3.4.3.

***Based on patient symptoms and overall clinical goals including avoidance of transfusion and improvement in anemia-related symptoms, and after exclusion

of active infection and other causes of ESA hyporesponsiveness.

s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s

3.3: We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy—inparticular when cure is the anticipated outcome—(1B), a history of stroke (1B), or a history of malignancy (2C).3.4.1: For adult CKD ND patients with Hb concentration Z10.0 g/dl (Z100 g/l), we suggest that ESA therapy not beinitiated (2D)

3.4.2: For adult CKD ND patients with Hb concentrationo10.0 g/dl (o100 g/l) we suggest that the decision whether toinitiate ESA therapy be individualized based on the rate of fall of Hb concentration, prior response to iron therapy,the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable toanemia (2C)

3.4.3: For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the Hb concentration fall below9.0 g/dl (90 g/l) by starting ESA therapy when the hemoglobin is between 9.0–10.0 g/dl (90–100 g/l) (2B)

3.4.4: Individualization of therapy is reasonable as some patients may have improvements in quality of life at higher Hbconcentration and ESA therapy may be started above 10.0 g/dl (100 g/l) (Not Graded)

3.4.5: For all pediatric CKD patients, we suggest that the selection of Hb concentration at which ESA therapy is initiated

in the individual patient includes consideration of potential benefits (e.g., improvement in quality of life, schoolattendance/performance, and avoidance of transfusion) and potential harms (2D)

ESA MAINTENANCE THERAPY

3.5.1: In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adultpatients with CKD (2C)

3.5.2: Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hbconcentration above 11.5 g/dl (115 g/l) and will be prepared to accept the risks (Not Graded)

3.6: In all adult patients, we recommend that ESAs not be used to intentionally increase the Hb concentration above

3.8.4: Re-evaluate ESA dose if (Not Graded):

K The patient suffers an ESA-related adverse event

K The patient has an acute or progressive illness that may cause ESA hyporesponsiveness (See Recommendations3.13.1–3.13.2)

EVALUATING AND CORRECTING PERSISTENT FAILURE TO REACH OR MAINTAIN INTENDED

HEMOGLOBIN CONCENTRATION

Frequency of monitoring

3.12.1: During the initiation phase of ESA therapy, measure Hb concentration at least monthly (Not Graded)

3.12.2: For CKD ND patients, during the maintenance phase of ESA therapy measure Hb concentration at least every 3months (Not Graded)

3.12.3: For CKD 5D patients, during the maintenance phase of ESA therapy measure Hb concentration at least monthly.(Not Graded)

Initial ESA hyporesponsiveness

3.13.1: Classify patients as having ESA hyporesponsiveness if they have no increase in Hb concentration from baselineafter the first month of ESA treatment on appropriate weight-based dosing (Not Graded)

3.13.2: In patients with ESA hyporesponsiveness, we suggest avoiding repeated escalations in ESA dose beyond double theinitial weight-based dose (2D)

Subsequent ESA hyporesponsiveness

3.14.1: Classify patients as having acquired ESA hyporesponsiveness if after treatment with stable doses of ESA, theyrequire 2 increases in ESA doses up to 50% beyond the dose at which they had been stable in an effort to maintain

a stable Hb concentration (Not Graded)

3.14.2: In patients with acquired ESA hyporesponsiveness, we suggest avoiding repeated escalations in ESA dose beyonddouble the dose at which they had been stable (2D)

Management of poor ESA responsiveness

3.15.1: Evaluate patients with either initial or acquired ESA hyporesponsiveness and treat for specific causes of poor ESAresponse (Not Graded)

3.15.2: For patients who remain hyporesponsive despite correcting treatable causes, we suggest individualization oftherapy, accounting for relative risks and benefits of (2D):

K decline in Hb concentration

K continuing ESA, if needed to maintain Hb concentration, with due consideration of the doses required, and

K blood transfusions

ADJUVANT THERAPIES

3.16.1: We recommend not using androgens as an adjuvant to ESA treatment (1B)

3.16.2: We suggest not using adjuvants to ESA treatment including vitamin C, vitamin D, vitamin E, folic acid,L-carnitine, and pentoxifylline (2D)

EVALUATION FOR PURE RED CELL APLASIA (PRCA)

3.17.1: Investigate for possible antibody-mediated PRCA when a patient receiving ESA therapy for more than 8 weeksdevelops the following (Not Graded):

K Sudden rapid decrease in Hb concentration at the rate of 0.5 to 1.0 g/dl (5 to 10 g/l) per week OR requirement

of transfusions at the rate of approximately 1 to 2 per week, AND

K Normal platelet and white cell counts, AND

K Absolute reticulocyte count less than 10,000/ml

3.17.2: We recommend that ESA therapy be stopped in patients who develop antibody-mediated PRCA (1A)

3.17.3: We recommend peginesatide be used to treat patients with antibody-mediated PRCA (1B)

s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s

Chapter 4: Red cell transfusion to treat anemia in CKD

USE OF RED CELL TRANSFUSION IN CHRONIC ANEMIA

4.1.1: When managing chronic anemia, we recommend avoiding, when possible, red cell transfusions to minimize thegeneral risks related to their use (1B)

4.1.2: In patients eligible for organ transplantation, we specifically recommend avoiding, when possible, red celltransfusions to minimize the risk of allosensitization (1C)

4.1.3: When managing chronic anemia, we suggest that the benefits of red cell transfusions may outweigh the risks inpatients in whom (2C):

K ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance)

K The risks of ESA therapy may outweigh its benefits (e.g., previous or current malignancy, previous stroke)4.1.4: We suggest that the decision to transfuse a CKD patient with non-acute anemia should not be based on anyarbitrary Hb threshold, but should be determined by the occurrence of symptoms caused by anemia (2C)

URGENT TREATMENT OF ANEMIA

4.2: In certain acute clinical situations, we suggest patients are transfused when the benefits of red cell transfusionsoutweigh the risks; these include (2C):

K When rapid correction of anemia is required to stabilize the patient’s condition (e.g., acute hemorrhage, unstablecoronary artery disease)

K When rapid pre-operative Hb correction is required

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Chapter 1: Diagnosis and evaluation of anemia

in CKD

Kidney International Supplements (2012) 2, 288–291; doi:10.1038/kisup.2012.33

TESTING FOR ANEMIA

BACKGROUND

In any individual, anemia may be the initial laboratory sign

of an underlying medical problem Consequently, a complete

blood count, including the hemoglobin (Hb) concentration,

is routinely part of global health assessment in most adults,

whether or not they have chronic kidney disease (CKD) In

patients with CKD but stable kidney function, the

appear-ance or progression of anemia may herald a new problem

that is causing blood loss or is interfering with red cell

production The anemia should be evaluated independently

of CKD stage in order to identify any reversible process

contributing to the anemia The causes of acquired anemia

are myriad and too many to include in a guideline such as

this A comprehensive list of causes and the approach to

diagnosis can be found in a standard textbook of medicine or

hematology The most commonly encountered reversible

cause of chronic anemia or worsening anemia in CKD

patients, other than anemia related directly to CKD, is iron

deficiency anemia

Frequency of testing for anemia

1.1.1: For CKD patients without anemia (as defined below

in Recommendation 1.2.1 for adults and

Recom-mendation 1.2.2 for children), measure Hb

concen-tration when clinically indicated and (Not Graded):

K at least annually in patients with CKD 3

K at least twice per year in patients with CKD

4–5ND

K at least every 3 months in patients with CKD

5HD and CKD 5PD

1.1.2: For CKD patients with anemia not being treated

with an ESA, measure Hb concentration when

clinically indicated and (Not Graded):

K at least every 3 months in patients with CKD

3–5ND and CKD 5PD

K at least monthly in patients with CKD 5HD

[See Recommendations 3.12.1–3.12.3 for

mea-surement of Hb concentration in patients being

treated with ESA.]

RATIONALE

Relatively little is known about the development and

progression of anemia in patients with CKD Consequently,

one cannot determine precisely the optimal frequency at

which Hb levels should be monitored The recommendationthat patients with CKD be periodically evaluated for anemiarests on observations that, in the absence of use oferythropoiesis-stimulating agents (ESAs), there often is agradual decline in Hb over time in patients with CKD as thelevel of glomerular filtration rate (GFR) declines,1suggestingthe need for regular surveillance of Hb concentration Thefrequency of Hb monitoring, regardless of CKD stage, should

be influenced by the Hb level (i.e., more frequent monitoringmay be appropriate in patients with more severe anemia) andrate of decline in Hb level As kidney function declines and inpatients with more advanced CKD stages, the incidence andprevalence of anemia increases Thus, in order to identifyCKD patients who may need intervention with ironadministration, an ESA, or even require a transfusion,more frequent monitoring of the Hb concentration will benecessary at later CKD stages

More frequent monitoring is recommended for adultCKD 5HD and CKD 5PD patients with anemia who are notreceiving an ESA; at least monthly in CKD 5HD patients and

at least every 3 months in CKD 5PD patients In CKD 5HDpatients, Hb monitoring is traditionally performed prior to amid-week hemodialysis (HD) session While this is notessential it probably does tend to minimize Hb variability due

to the longer inter-dialytic interval between the last treatment

of one week and the first of the next As in all patients, Hbtesting should be performed whenever clinically indicated,such as after a major surgical procedure, hospitalization, orbleeding episode

In the pediatric population with CKD, there is no directevidence to recommend a different frequency of monitoringfor anemia than for adults In the Chronic Kidney Disease inChildren Prospective Cohort Study (CKiD), which evaluated

340 North American children with CKD using determined GFR,2 below a GFR threshold of 43 ml/min per1.73 m2, there was a linear relationship between Hb and GFR,with Hb 0.3 g/dl (3 g/l) lower per 5 ml/min per 1.73 m2lowerGFR Above that threshold, there was a nonsignificantassociation of 0.1 g/dl (1 g/l) lower Hb for every 5 ml/minper 1.73 m2 lower GFR Because serum creatinine-basedestimated glomerular filtration rate (eGFR) using theSchwartz formula may overestimate the true GFR in thechildren3 providers need to consider the potential for

iohexol-Hb decline and anemia even at early stages of CKD andmonitor accordingly In children with CKD 5HD andCKD 5PD, monthly monitoring for anemia is standardclinical practice

& 2012 KDIGO

Diagnosis of anemia

1.2.1: Diagnose anemia in adults and children 415 years

with CKD when the Hb concentration iso13.0 g/dl

(o130 g/l) in males and o12.0 g/dl (o120 g/l) in

females (Not Graded)

1.2.2: Diagnose anemia in children with CKD if Hb

concentration is o11.0 g/dl (o110 g/l) in children

0.5–5 years, o11.5 g/dl (115 g/l) in children 5–12

years, and o12.0 g/dl (120 g/l) in children 12–15

years (Not Graded)

RATIONALE

The Hb concentration values that define anemia and should

lead to initiation of an evaluation for the cause of anemia

are dependent on sex and age The recommended Hb values

for adults and children represent the World Health

Organization (WHO) definition of anemia and establish a

benchmark for anemia workup that has been applied across

populations.4

An alternative source for Hb concentration values that

define anemia in children between 1 and 19 years is based on

US National Health and Nutrition Examination Survey III

(NHANES III) data from 1988–945 (Table 1) For children

between birth and 24 months, the data are taken from

normal reference values6(Table 2)

These thresholds for diagnosis of anemia and evaluation

for the causes of anemia should not be interpreted as being

thresholds for treatment of anemia Rather than relying on a

single laboratory test value, in patients without an apparent

cause for a low Hb level, the value should be confirmed to be

below the threshold values for diagnosis of anemia prior to

initiating a diagnostic work up

Investigation of anemia1.3: In patients with CKD and anemia (regardless of ageand CKD stage), include the following tests in initialevaluation of the anemia (Not Graded):

K Complete blood count (CBC), which shouldinclude Hb concentration, red cell indices, whiteblood cell count and differential, and platelet count

K Absolute reticulocyte count

K Serum ferritin level

K Serum transferrin saturation (TSAT)

K Serum vitamin B12and folate levels

RATIONALEComplete blood count

The complete blood count (CBC) provides informationabout the severity of anemia and adequacy of bone marrowfunction Severity of anemia is assessed best by measuring Hb

Table 1 | Hb levels in children between 1–19 years for initiation of anemia workupa

All races/ethnic

groups

Number of subjects

Mean Hb g/dl (g/l)

Standard deviation g/dl (g/l)

Anemia definition met if value is o5 th

percentile g/dl (g/l) Boys

Menstrual losses contribute to lower mean and 5 th

percentile Hb values for group.

Table 2 | Hb levels in children between birth and 24 monthsfor initiation of anemia workupa

Age Mean Hb g/dl (g/l) 2 SDbg/dl (g/l) Term (cord blood) 16.5 (165) 13.5 (135) 1–3 d 18.5 (185) 14.5 (145)

1 wk 17.5 (175) 13.5 (135)

2 wk 16.5 (165) 12.5 (125)

1 mo 14.0 (140) 10.0 (100)

2 mo 11.5 (115) 9.0 (90) 3–6 mo 11.5 (115) 9.5 (95) 6–24 mo 12.0 (120) 10.5 (105)

d, day; Hb, hemoglobin; mo, month; SD, standard deviation; wk, week.

a

Data taken from normal reference values This was published in Nathan DG, Orkin

SH Appendix 11: Normal hematologic values in children In: Nathan DG, Orkin SH, Ginsburg D et al (eds) Nathan and Oski’s Hematology of Infancy and Childhood, 6th edn p 1841, & Elsevier, 2003 6

b

Values 2 standard deviations below the mean are equivalent to o2.5 th

percentile.

c h a p t e r 1

concentration rather than hematocrit The latter

measure-ment is a relatively unstable analyte and its measuremeasure-ment

lacks standardization and is instrumentation dependent,

since it is derived indirectly by automated analyzers.7–9There

is no evidence to support any different recommendation for

the initial evaluation of anemia for children compared to

adults

In addition to Hb concentration, other reported results of

the CBC may convey important clinical information The

anemia of CKD is hypoproliferative, and in general,

normochromic and normocytic In this regard it is

morphologically indistinguishable from the anemia of

chronic disease.10 Folate or vitamin B12 deficiencies may

lead to macrocytosis, whereas iron deficiency or inherited

disorders of Hb formation (e.g., a- or b-thalassemia) may

produce microcytosis Iron deficiency, especially if

long-standing, is associated with hypochromia (low mean

corpuscular hemoglobin [MCH]) Macrocytosis with

leuko-penia or thrombocytoleuko-penia suggests a generalized disorder of

hematopoiesis caused by toxins (e.g., alcohol), nutritional

deficit (vitamin B12or folate deficiency), or myelodysplasia

When these findings are present, further diagnostic

evalua-tion may be indicated

The low erythropoietic activity that characterizes the

anemia of CKD is consistent with insufficient erythropoietin

stimulation Erythropoietin levels are not routinely used in

distinguishing erythropoietin deficiency from other causes of

anemia in patients with CKD in most clinical settings and

their measurement is generally not recommended.11,12

Effective erythropoietic proliferative activity is most simply

assessed by determination of the absolute reticulocyte count

Abnormalities of the white blood cell count and differential

or platelet count are not typical of the anemia of CKD and

should prompt investigation for other processes

Reticulocyte count, which may be obtained with

auto-mated CBC testing, may be high in patients who have active

blood loss or hemolysis, and may be low in hypoproliferative

erythropoiesis with anemia

Iron status

There are two important and distinct aspects of the

assessment of iron status testing: the presence or absence of

storage iron and the availability of iron to support ongoing

erythropoiesis The serum ferritin is the most commonly

used test for evaluation of storage iron, for which the ‘gold

standard’ remains examination of a bone marrow aspiration

stained for iron.13The transferrin saturation (TSAT; serum

iron 100 divided by total iron binding capacity) is the most

commonly used measure of the availability of iron to support

erythropoiesis The serum ferritin is affected by inflammation

and is an ‘acute phase reactant’13 and, thus, ferritin values

have to be interpreted with caution in CKD patients,

especially those on dialysis in whom subclinical inflammation

may be present.14

Serum ferritin values r30 ng/ml (r30 mg/l) indicate

severe iron deficiency and are highly predictive of absent

iron stores in bone marrow.15,16 Ferritin values 430 ng/ml(430 mg/l), however, do not necessarily indicate the presence

of normal or adequate bone marrow iron stores Studiesassessing ferritin levels above which all or nearly all patientswith CKD have normal bone marrow iron stores haveproduced varied results but most CKD patients, includingthose who are on HD, will have normal bone marrow ironstores when their serum ferritin level is Z300 ng/ml(Z300 mg/l) Even at serum ferritin levels of 100 ng/ml(100 mg/l) most CKD patients have stainable bone marrowiron stores.16–21As will be discussed in Chapter 2, the serumferritin and TSAT values are often used together to assess ironstatus, diagnose iron deficiency, and predict an erythropoieticresponse to iron supplementation (Supplementary Table 1online)

Other tests of iron status, such as percentage ofhypochromic red blood cells and reticulocyte Hb contentmay be used instead of, or in addition to, TSAT and ferritinlevels if available Measurement of hepcidin levels has notbeen shown to be clinically useful or superior to morestandard iron status tests in patients with CKD.22,23

Vitamin B12and folate

Folate and vitamin B12 deficiency are uncommon butimportant causes of treatable anemia, typically associatedwith macrocytic red blood cell (RBC) indices Limited dataindicate a prevalence of vitamin B12and folate deficiency inr10% of HD patients; the prevalence in CKD patients

is not known Nonetheless, since these deficiencies are easilycorrectable, and in the case of vitamin B12 may indicateother underlying disease processes, assessment of folateand vitamin B12 levels are generally considered standardcomponents of anemia evaluation, especially in thepresence of macrocytosis Folate deficiency is best detected

in most patients with serum folate level testing; RBC folatelevels can be measured when serum folate levels are equivocal

or when there is concern that recent dietary intake mayobscure underlying folate deficiency using serum levelsalone.24

Additional tests

Other tests, in addition to those indicated above, may beappropriate in individual patients and in certain specificclinical settings For instance measurement of high sensitivityC-reactive protein (CRP) may be indicated if occultinflammation is a concern In certain countries and/or inpatients of specific nationalities or ethnicities, testing forhemoglobinopathies, parasites, and other conditions may beappropriate

c h a p t e r 1

butor, copyright holder, or advertiser concerned

Accord-ingly, the publishers and the ISN, the editorial board and

their respective employers, office and agents accept no

liability whatsoever for the consequences of any such

inaccurate or misleading data, opinion or statement While

every effort is made to ensure that drug doses and other

quantities are presented accurately, readers are advised that

new methods and techniques involving drug usage, and

described within this Journal, should only be followed inconjunction with the drug manufacturer’s own publishedliterature

Chapter 2: Use of iron to treat anemia in CKD

Kidney International Supplements (2012) 2, 292–298; doi:10.1038/kisup.2012.34

TREATMENT WITH IRON AGENTS

BACKGROUND

Correction of iron deficiency with oral or intravenous iron

supplementation can reduce the severity of anemia in

patients with CKD.25,26 Untreated iron deficiency is an

important cause of hyporesponsiveness to ESA treatment.27,28

It is important to diagnose iron deficiency because treatment

can readily correct the associated anemia and investigation

for the cause of iron deficiency, which should follow its

detection, can lead to important diagnoses In the absence of

menstrual bleeding, iron depletion and iron deficiency

usually result from blood loss from the gastrointestinal

tract There are additional considerations in CKD patients

with iron deficiency For instance, hemodialysis patients

are subject to repeated blood loss due to retention of blood in

the dialyzer and blood lines Other contributing causes in

hemodialysis and other CKD patients include frequent

blood sampling for laboratory testing, blood loss from

surgical procedures (such as creation of vascular access),

interference with iron absorption due to medications

such as gastric acid inhibitors and phosphate binders,

and reduced iron absorption due to inflammation.29 The

reader is referred to standard textbooks of medicine and

pediatrics for more extensive discussions on the diagnosis

and evaluation of patients with known or suspected iron

deficiency

Iron supplementation is widely used in CKD patients

to treat iron deficiency, prevent its development in

ESA-treated patients, raise Hb levels in the presence or absence

of ESA treatment, and reduce ESA doses in patients receiving

ESA treatment Iron administration is appropriate when

bone marrow iron stores are depleted or in patients who are

likely to have a clinically meaningful erythropoietic response

It is prudent, however to avoid iron therapy in patients

in whom it is unlikely to provide meaningful clinical

benefit, i.e., avoid transfusion and reduce anemia-related

symptoms, and in those in whom potential benefit is

outweighed by risks of treatment.23,30–32 There are relatively

few data on the long-term clinical benefits of iron

supplementation other than direct effects on the Hb

concentration There is similarly little information on the

long-term adverse consequences of iron supplementation in

excess of that necessary to provide adequate bone marrow

iron stores.33–35Since bone marrow aspiration for assessment

of iron stores is rarely done in clinical practice, iron

supplementation is typically assessed by blood-based iron

status tests without knowledge of bone marrow iron

2.1.2: For adult CKD patients with anemia not on iron orESA therapy we suggest a trial of IV iron (or in CKD

ND patients alternatively a 1–3 month trial of oraliron therapy) if (2C):

K an increase in Hb concentration without ing ESA treatment is desired* and

start-K TSAT is r30% and ferritin is r500 ng/ml(r500 mg/l)

2.1.3: For adult CKD patients on ESA therapy whoare not receiving iron supplementation, we suggest

a trial of IV iron (or in CKD ND patientsalternatively a 1–3 month trial of oral iron therapy)

if (2C):

K an increase in Hb concentration** or a decrease

in ESA dose is desired*** and

K TSAT is r30% and ferritin is r500 ng/ml(r500 mg/l)

2.1.4: For CKD ND patients who require iron tation, select the route of iron administrationbased on the severity of iron deficiency, availability

supplemen-of venous access, response to prior oral irontherapy, side effects with prior oral or IViron therapy, patient compliance, and cost (NotGraded)

2.1.5: Guide subsequent iron administration in CKDpatients based on Hb responses to recent irontherapy, as well as ongoing blood losses, iron statustests (TSAT and ferritin), Hb concentration, ESAresponsiveness and ESA dose in ESA treatedpatients, trends in each parameter, and the patient’sclinical status (Not Graded)

& 2012 KDIGO

*Based on patient symptoms and overall clinical goals, including avoidance

of transfusion, improvement in anemia-related symptoms, and after exclusion of active infection.

**Consistent with Recommendations #3.4.2 and 3.4.3.

***Based on patient symptoms and overall clinical goals including avoidance

of transfusion and improvement in anemia-related symptoms, and after exclusion of active infection and other causes of ESA hyporesponsiveness.

2.1.6: For all pediatric CKD patients with anemia not on

iron or ESA therapy, we recommend oral iron (or IV

iron in CKD HD patients) administration when

TSAT is r20% and ferritin is r100 ng/ml

(r100 lg/l) (1D)

2.1.7: For all pediatric CKD patients on ESA therapy who

are not receiving iron supplementation, we

recom-mend oral iron (or IV iron in CKD HD patients)

administration to maintain TSAT 420% and

ferritin 4100 ng/ml (4100 lg/l) (1D)

RATIONALE

In patients with CKD-associated anemia, iron

supplementa-tion is intended to assure adequate iron stores for

erythro-poiesis, correct iron deficiency, and, in patients receiving ESA

treatment, prevent iron deficiency from developing Iron

supplementation, particularly with intravenous iron, can

enhance erythropoiesis and raise Hb levels in CKD patients

with anemia even when TSAT and ferritin levels are not

indicative of absolute iron deficiency, and even when bone

marrow studies reveal adequate iron stores.38–40 Iron

treatment, particularly when administered intravenously,

has also been consistently demonstrated to improve the

erythropoietic response to ESA treatment.27,28,32,36,37,41–43For

any individual patient the optimal balance of Hb level, ESA

dose, and iron dose at which clinical benefit is maximized

and potential risk is minimized is not known Prescribing

iron therapy for CKD patients is complicated by the relatively

poor diagnostic utility of serum ferritin and TSAT tests to

estimate body iron stores or for predicting a Hb response to

iron supplementation.23,30Even examination of bone marrow

iron stores, considered the ‘gold standard’ for assessment of

iron stores, does not predict erythropoietic responsiveness to

iron supplementation in patients with CKD with a high

degree of accuracy.16,23,30,40 It is important that the

short-and long-term safety of oral short-and intravenous (IV) iron

agents, when known, be carefully considered when iron

therapy is prescribed, and that the potential for as yet

undiscovered toxicities also be taken into account In each

patient there must be consideration of current and desired

Hb level, ESA dose and trends in ESA dose over time,

assessment of the Hb response to iron supplementation,

ongoing blood loss, and changes in iron status tests While

observational studies have not for the most part produced

strong evidence of significant toxicity of chronic IV iron

administration, the clinical benefit of such treatment has also

not been convincingly demonstrated, although a recent

randomized controlled trial (RCT) in patients with heart

failure (some of whom also had mild CKD) is encouraging.44

TSAT and ferritin levels

The two most widely available tests for assessing iron status

are the TSAT and serum ferritin level A very low serum

ferritin (o30 ng/ml [o30 mg/l]) is indicative of iron

deficiency.16 Except in this circumstance, the TSAT and

serum ferritin level have only limited sensitivity and

specificity in patients with CKD for prediction of bonemarrow iron stores and erythropoietic response to ironsupplementation16-21,40,45 (Figures 1 and 2) Their utility isfurther compromised by substantial inter-patient variabilityunrelated to changes in iron store status.46

Evidence to support a recommendation for specific TSATand ferritin levels at which iron therapy should be initiated or

as ‘targets’ for iron therapy is limited, with very fewRCTs.16–21No iron intervention trials have been sufficientlypowered or of long enough duration to assess long-termsafety and no studies have addressed the clinical benefit, cost-effectiveness, and risk-benefit comparison of using differentTSAT and ferritin levels for the diagnosis of iron deficiency or

as a trigger for iron supplementation

The Work Group sought to recommend iron targets thatbalance diagnostic sensitivity and specificity with assump-tions regarding safety Previous clinical practice recommen-dations (Kidney Diseae Outcomes Quality Initiative[KDOQI] 2006 and others), largely opinion-based, indicatedthat supplemental iron should be administered to maintainferritin levels 4200 ng/ml (4200 mg/l) in CKD 5HD patientsand 4100 ng/ml (4100 mg/l) in CKD ND and CKD 5PDwith TSAT 420% in all CKD patients These guidelines alsoindicated that there was insufficient evidence to recommendroutine IV iron administration when the ferritin level was

4500 ng/ml (4500 mg/l)

Most CKD patients with serum ferritin levels 4100 ng/ml(4100 mg/l) have normal bone marrow iron stores,16–21 yetmany such patients will also have an increase in Hbconcentration and/or reduction in ESA dose if supplementaliron is provided.16,23,30,31,40,45A substantial fraction of CKDpatients with anemia and TSAT 420% respond to ironsupplementation with an increase in Hb concentration and/

Figure 1 | Receiver operating characteristic (ROC) curves, examining the utility of iron status tests to distinguish iron deficient from nondeficient study patients Reprinted with permission from Macmillan Publishers Ltd: Kidney International Van Wyck DB, Roppolo M, Martinez CO et al A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD Kidney Int 2005; 68: 2846–2856; 45 accessed http://www.nature.com/ki/journal/v68/n6/ full/4495631a.html.

c h a p t e r 2

or reduction in ESA dose Therefore, for patients who have

not been receiving iron supplementation, we suggest iron

administration in anemic CKD patients with TSAT o30%

and serum ferritino500 ng/ml (o500 mg/l) if an increase in

Hb level is desired, particularly if intended to avoid

transfusions and reduce anemia-related symptoms, and/or

reduction in ESA dose, after consideration of the potential

risks of iron administration The safety of providing

additional iron to intentionally maintain TSAT 430% and

serum ferritin 4500 ng/ml (4500 mg/l) has been studied in

very few patients We do not recommend routine use of iron

supplementation in patients with TSAT 430% or serum

ferritin 4500 ng/ml (4500 mg/l) since, as stated above, the

benefits and risks of doing so are inadequately studied In all

patients receiving iron, it is important to weigh both

short-term and acute toxicities associated with iron therapy and

exclude the presence of active infection (Recommendation

2.4) before embarking on a course of IV iron treatment

There is only very limited evidence in patients with CKD

that informs any decision about defining any specific upper

limits for iron status targets in guiding iron treatment.47,48

Previous guidelines, such as the 2006 KDOQI guidelines and

others, have specified serum ferritin levels above which

additional IV iron therapy was generally not

recom-mended,8,49–52 usually citing limits of 500–800 ng/ml

(500–800 mg/l) However, no RCTs and few other studies

have examined the efficacy and safety of providing IV iron to

maintain ferritin levels 4500–800 ng/ml (4500–800 mg/l).Most studies are retrospective and the few prospective studieshave had small numbers of patients and short follow up,using surrogate outcomes such as Hb and ESA dose ratherthan more meaningful patient outcomes such as infectionrisk and mortality In most patients with TSAT 430% orserum ferritin 4500 ng/ml (4500 mg/l), any erythropoieticresponsive to iron supplementation alone (i.e., the incre-mental change in Hb and/or reduction in ESA dose) will besmall In one RCT conducted in CKD 5HD patients withanemia, serum ferritin 500–1200 ng/ml (500–1200 mg/l), andTSATo25%, patients received a 25% increase in epoetin doseand were randomly assigned to receive either no iron(control) or 1000 mg IV iron At 6 weeks, Hb increased to

a greater extent in the IV iron group.53 This study was notconsidered in the choice of target levels for ferritin and TSAT

in this guideline in part because it studied only a restrictedgroup of patients, all of whom also received an increase inESA dose The number of patients was too small and theperiod of observation too short to assess either clinicallyimportant outcomes or toxicity in a meaningful way(Supplementary Tables 2–4 online)

High ferritin levels in some studies have been associatedwith higher death rates, but whether elevation of ferritinlevels is a marker of excessive iron administration rather than

a nonspecific acute phase reactant is not clear At increasinglyhigher ferritin levels, there is some evidence to indicate thathepatic deposition of iron increases.54,55 Clinical sequelae ofthis have not been documented although such hepatic irondeposition might be of particular concern in patients withhepatitis C virus (HCV) infection.56 While some data areavailable linking ferritin levels in patients with hemochro-matosis and transfusional tissue iron deposition in patientswithout CKD,57it is not clear to what extent these findingsare relevant to CKD patients or should be used to guideclinical practice in CKD patients

Rather than focusing on serum ferritin levels as a predictor

of outcomes, some observational studies have examinedassociations between patient outcomes and amount of ironadministered One such study found no adverse associationbetween 2-year survival when the IV iron dose over 6 monthswasr1000 mg, but a statistically significant higher mortalityfor iron doses 41000 mg (adjusted hazards ratio [HR] 1.09;95% confidence interval [CI] 1.01–1.17 for 4 1000 mg to

1800 mg and 1.18; 95% CI 1.09–1.27 for 4 1800 mg).33ever, after using multivariable models accounting fortime-varying measures of iron administration and otherparameters, there was no statistically significant associationbetween any level of iron administration and mortality.Another retrospective study using time-dependent and multi-variate adjustment for case mix found that IV iron doses up to

How-400 mg/month were associated with lower death ratescompared to doses 4400 mg/month35 (Supplementary Table

5 online)

It is the consensus of the Work Group that additional IViron should not routinely be administered in patients with

Figure 2 | Sensitivity and specificity of TSAT and serum ferritin

(ferritin) and their combination (TSAT þ ferritin) and bone

marrow iron (BM iron) to identify correctly a positive

erythropoietic response (Z1-g/dl [Z10-g/l] increase in Hb

[DHb]) to intravenous iron in 100 nondialysis patients with

CKD (areas under the ROCs) Reproduced with permission from

American Society of Nephrology 40 from Stancu S, Barsan L,

Stanciu A et al Can the response to iron therapy be predicted in

anemic nondialysis patients with chronic kidney disease? Clin J Am

Soc Nephrol 2010; 5: 409–416; permission conveyed through

Copyright Clearance Center; accessed http: http://

cjasn.asnjournals.org/content/5/3/409.long

c h a p t e r 2

serum ferritin levels that are consistently 4500 ng/ml

(4500 mg/l) In patients with Hb below the desired level

who are receiving relatively high ESA doses, or in whom

discontinuation of ESA therapy is preferred (for instance a

CKD patient with malignancy), a therapeutic trial of

additional IV iron (i.e., a single course of up to 1000 mg

over a period of several weeks which can be repeated as

needed) may be undertaken in patients with serum ferritin

levels 4500 ng/ml (4500 mg/l) after due consideration of

potential acute toxicities and long-term risks Subsequent

treatment decisions should be based on the patient’s clinical

status, including trends in TSAT, ferritin, and Hb level, and

ESA dose and responsiveness

Ferritin levels need to be interpreted with caution in

patients who may have an underlying inflammatory

condi-tion as they may not predict iron stores or responsiveness to

iron therapy in a manner similar to that when inflammation

is absent In the absence of a clinically evident infectious or

inflammatory process, assessment of CRP may suggest the

presence of an occult inflammatory state that may be

associated with an elevated ferritin level and

ESA-hypor-esponsiveness (Supplementary Table 6 online)

Other iron status tests not as widely available as TSAT and

ferritin such as percentage of hypochromic red cells,

reticulocyte Hb content, zinc protoporphyrin, and soluble

transferrin receptors may be used to assess iron status, but are

less well studied.22,23

There is no evidence that a higher ferritin target of 200

ng/ml (200 mg/l) is the appropriate or inappropriate

cutoff in CKD 5HD pediatric patients Consequently no

change has been made to the 2006 KDOQI guideline in

children with CKD and anemia, which recommended a

ferritin target greater than 100 ng/ml (100 mg/l) for CKD

5HD, as well as for CKD 5PD and CKD ND who are not on

ESA therapy.58

Iron treatment

A decision to provide an individual patient with iron therapy

should be based on an assessment that an increase in Hb level

is desirable, that is, to avoid transfusions or reduce

anemia-related symptoms, and that the potential adverse effects of

iron supplementation, either oral or IV, have been considered

and are appropriately outweighed by the expected treatment

benefit Such supplementation could be in the form of oral or

intravenous iron Use of intramuscular iron has largely been

abandoned Each route has its own potential advantages and

disadvantages Oral iron is inexpensive, readily available, and

does not require IV access, a particular concern in CKD

patients not on HD It is also not associated with severe

adverse effects but gastrointestinal side effects are common

and may limit adherence This, along with variable

gastro-intestinal tract absorption, limits the efficacy of oral iron IV

iron avoids concerns about medication adherence and

efficacy in treating iron deficiency, but requires IV access

and has been associated with infrequent but severe adverse

reactions Decisions about the preferred route of iron

supplementation should take into consideration severity ofanemia and iron deficiency, the response, tolerance andadherence to prior oral iron administration, costs, and ease ofobtaining venous access balanced against the desire topreserve venous access sites

In patients with CKD ND, the available evidence supports

an efficacy advantage of IV compared with oral tion of iron although the effect is rather small, with aweighted mean Hb difference of 0.31 g/dl (3.1 g/l).45,59–63Whether the small Hb benefit of IV iron in CKD ND patients

administra-is clinically meaningful or justifies the small radministra-isk of seriousadverse events and unknown long-term risks is uncertain.The consensus of the Work Group is that a clearly definedadvantage or preference for IV compared to oral iron was notsupported by available evidence in CKD ND patients.Therefore, in such patients, the route of iron administrationcan be either IV or oral In some patients the desire to avoidvenipuncture (and preserve IV access) may favor in somepatients, particularly those with mild iron deficiency, aninitial trial of oral iron

Oral iron is typically prescribed to provide approximately

200 mg of elemental iron daily (for instance ferrous sulfate

325 mg three times daily; each pill provides 65 mg elementaliron) Smaller daily doses may be useful and better tolerated

in some patients Although ferrous sulfate is commonlyavailable and inexpensive, other oral iron preparationsmay also be used; there is not significant evidence to suggestthat other oral iron formulations are more effective orassociated with fewer adverse side effects than ferroussulfate If the goals of iron supplementation are not metwith a 1–3 month course of oral iron, it is appropriate toconsider IV iron supplementation in a manner consistentwith the above recommendation statements and the discus-sion that follows

There is evidence supporting a preference for the IVroute of iron administration in CKD 5HD patientsderived from RCTs and other studies comparing IV ironwith oral iron and placebo, with and without concomitantESA treatment.27,32,62,64,65 In most of these studies,

IV iron administration led to a greater increase in Hbconcentration, a lower ESA dose, or both In CKD 5HDpatients, the ready IV access and convenience of being able toadminister IV iron during HD treatments further supportsthe preference for the IV route for iron administration inthese patients

In prior CKD anemia guidelines,50 CKD 5PD patientswere considered more similar to CKD ND than CKD 5HD intheir need for and likely responsiveness to iron, as well as intheir absence of ready venous access for IV iron administra-tion Limited studies of iron administration in CKD5PD patients indicate that oral iron is of limited efficacyand that IV iron is superior to oral iron in terms of achieved

Hb level and ESA dose Consequently, this route is preferred

in these patients, although the desire to preserve potentialfuture venous access sites must be considered in suchpatients.66–70

c h a p t e r 2

IV iron may be provided as a single large dose or as

repeated smaller doses depending on the specific IV iron

preparation used (with the highest single dose varying by

specific formulation) It is common practice to provide an

initial course of IV iron amounting to approximately

1000 mg; this may be repeated if an initial dose fails to

increase Hb level and/or allow a decrease in ESA dose and if

the TSAT remains r30% and serum ferritin remains

r500 ng/ml (r500 mg/l).38

Decisions regarding continued iron therapy should take

into consideration recent patient responses to iron therapy,

iron status tests (TSAT and ferritin), Hb concentration, ESA

responsiveness and ESA dose in ESA-treated patients,

ongoing blood losses, trends in each parameter, and the

patient’s clinical status Serum ferritin and TSAT levels

should not be measured until at least one week has elapsed

since the most recent prior IV iron dose Consideration of

expected iron needs and evaluation for ongoing iron losses

should precede further IV iron administration Blood loss

should be minimal in CKD ND and CKD 5PD patients, while

CKD 5HD patients have reported to lose between 1–2 gm of

iron per year related to the HD procedure and related

circumstances.71–73Thus, an apparent ongoing need for any

iron supplementation in CKD ND and CKD 5PD patients or

for more than 1–2 gm/yr in CKD 5HD patients should

prompt assessment for a source of active blood loss The need

to consider trends in iron status tests are highlighted by

consideration of a patient with decreasing TSAT and ferritin

levels which may signify the presence of gastrointestinal

bleeding or excessive dialysis-associated blood loss As

another example, an increasing TSAT and ferritin level may

indicate excessive iron supplementation and a need to

decrease or discontinue iron administration Finally, an

increase in ferritin level accompanied by a decrease in TSAT

and Hb level suggests inflammation-mediated

reticuloen-dothelial blockade.14

There are two commonly used approaches to ongoing

or maintenance IV iron treatment in CKD 5HD patients:

(1) periodic iron repletion, consisting of a series of IV iron

doses administered episodically to replenish iron stores

whenever iron status tests indicate the likelihood of iron

deficiency or decrease below specific target levels; or (2)

maintenance treatment, consisting of smaller doses

adminis-tered at regular intervals to maintain iron status tests stable

within specific limits with the intent of avoiding iron

deficiency or decline of iron test parameters below specific

levels Limited evidence suggests that regular maintenance IV

iron administration in CKD 5HD is associated with use of

lower ESA doses and may result in lower cumulative iron

doses41,74,75 but these data are insufficient to support a

recommendation favoring any particular IV iron dosing

strategy in this patient population By nature of the clinical

encounters with CKD 5PD patients, IV iron supplementation

is often provided at periodic (e.g., monthly) visits

Overall, the TSAT and ferritin recommendations above are

applicable to children with CKD on ESA therapy However,

there is no evidence that a higher ferritin target of 200 ng/ml(200 mg/l) is the appropriate or inappropriate cutoff inpediatric CKD HD patients Consequently no change hasbeen made to the 2006 KDOQI guideline in CKD in childrenwith anemia, which recommended a ferritin target greaterthan 100 ng/ml (100 mg/l) for CKD 5HD, as well as for CKD5PD and CKD ND who are on ESA therapy.58

IRON STATUS EVALUATION2.2.1: Evaluate iron status (TSAT and ferritin) at leastevery 3 months during ESA therapy, including thedecision to start or continue iron therapy (NotGraded)

2.2.2: Test iron status (TSAT and ferritin) more frequentlywhen initiating or increasing ESA dose, whenthere is blood loss, when monitoring response after

a course of IV iron, and in other circumstanceswhere iron stores may become depleted (NotGraded)

RATIONALE

In the absence of clinical trials that specifically informthe optimal frequency for testing of iron status, andconsistent with prior guidelines,50the consensus of the WorkGroup is that patients who are on ESA therapy, regardless ofwhether iron treatment is also being used, should have tests

of iron status at least every 3 months Falling TSAT and/orferritin levels are likely to reflect ongoing blood loss orconsumption of available iron stores, and can be used toanticipate the need for future or additional iron supplemen-tation In patients on oral iron treatment, iron status testingcan also be used to assess adherence with iron treatment.Increasing TSAT and/or ferritin levels may indicate that irontreatment is excessive and can be stopped or reduced.Increasing ferritin levels in association with stable ordeclining TSAT levels may also indicate the presence ofinflammation, infection, or other clinical situations inducingacute phase reactants during which time the appropriate-ness of continued iron administration may need to bereassessed.14

In some circumstances, more frequent iron status testingmay be appropriate, including following initiation of ESA oriron therapy or when the ESA dose or dose frequency isincreased Iron status testing is also important in theassessment of patients who become less responsive to ESAtreatment

Despite the absence of specific data in the pediatric CKDpopulation, this recommendation is considered applicable tochildren since there are no reasons to suggest a differentrecommendation Since the 2006 KDOQI guideline foranemia in pediatric CKD,58no new evidence regarding irontherapy for children with CKD has been published Thesuggestion for oral iron supplementation in children is2–6 mg/kg/day of elemental iron in 2–3 divided doses.76,77AnRCT of 35 iron replete pediatric CKD 5HD patients evaluated

c h a p t e r 2

their response to either weekly IV iron dextran dosed by

weight or oral iron 6 mg/kg/day Only the IV iron dextran

produced a significant increase in the serum ferritin levels

and showed a significant decrease in ESA dose required to

maintain target Hb levels.78 An international multicenter

double-blind RCT investigated the safety and efficacy of two

dosing regimens (1.5 mg/kg or 3 mg/kg) of ferric gluconate in

iron-deficient pediatric hemodialysis patients receiving

con-comitant ESA therapy Efficacy and safety profiles were

comparable, with no unexpected adverse events with either

dose.79 Based on this trial, the recommendation for initial

ferric gluconate therapy is 1.5 mg/kg for eight doses for

iron-deficient pediatric CKD 5HD patients and 1 mg/kg per

week for iron-replete pediatric CKD 5HD patients, with

subsequent dose adjustments made according to TSAT

and/or ferritin levels.79,80 Iron sucrose has also been used in

children with CKD81 but, as of yet, no RCTs have been

published in this population Although it is not uncommon

that pediatric CKD 5PD and CKD ND patients either do not

respond to or tolerate oral iron therapy, the need for IV access

for parenteral iron therapy often limits its utilization in

children

CAUTIONS REGARDING IRON THERAPY

2.3: When the initial dose of IV iron dextran is

adminis-tered, we recommend (1B) and when the initial dose

of IV non-dextran iron is administered, we suggest

(2C) that patients be monitored for 60 minutes after

the infusion, and that resuscitative facilities (including

medications) and personnel trained to evaluate and

treat serious adverse reactions be available

RATIONALE

Any form of IV iron may be associated with potentially

severe acute reactions.82–91 The symptoms of most concern

are hypotension and dyspnea, which in the worst cases may

be catastrophic with features of anaphylaxis The cause

of reactions has not been fully characterized, but may

involve immune mechanisms and/or release of free,

reactive iron into the circulation with induction of oxidative

stress The mechanisms of acute reactions may differ for

different iron preparations Certain iron dextrans in

parti-cular have been associated with reactions characteristic of

anaphylaxis The rate of such reactions is estimated to occur

in 0.6–0.7% of patients treated The serious adverse effect

event rate may be lower with low molecular weight iron

dextran compared to high molecular weight iron

dex-tran.92–96

With non-dextran IV iron drugs, it is believed that

anaphylactoid and other severe and potentially

life-threaten-ing reactions are less common, but this has not been well

substantiated Serious reactions including profound

hypo-tension do occur, even if uncommonly, with all non-dextran

IV iron preparations Because all forms of IV iron drugs can

be associated with serious immediate reactions, they should

be used with vigilance Since the rate of such reactionsmay be greater for iron dextran drugs we recommendthat resuscitative medications and personnel trained toevaluate and treat serious adverse reactions be availablewhen the initial dose of IV iron dextran is administered.The data to support such a recommendation for the initialdose of non-iron dextran compounds is not as strong In the

US, the Food and Drug Administration (FDA)-mandatedlabeling for ferumoxytol specifies that patients be observedfor 60 minutes after administration This may be reasonableadvice for all IV iron drugs, including other new ironpreparations such ferric carboxymaltose and iron isomalto-side For each IV iron preparation prescribing physiciansshould be familiar with the drug’s safety and toxicity profileand the product labeling warnings and recommendationsfor administration, as well as patient monitoring during andafter treatment

Iron during infection2.4: Avoid administering IV iron to patients with activesystemic infections (Not Graded)

RATIONALE

Iron is essential for the growth and proliferation of mostpathogens including many bacteria, viruses, fungi, parasitesand helminthes, and also exerts subtle effects on immunefunction and host responses towards microbes.97 There istheoretical and experimental evidence to suggest that ironadministration may worsen an existing infection but clinicalevidence is lacking In animal models, iron overload results in

an impaired control of infections, specifically with lular bacteria or fungi.98–101In humans, tissue iron overloadhas been considered as a risk factor for the acquisition ofcertain infections and for an unfavorable clinical course ofthe infection Data in CKD patients are conflicting.102–104Since current evidence cannot provide a clear answer as towhether specific CKD patient groups are at increased risk forinfection, or of having a poorer outcome with infection whenanemia is treated with IV iron, the Work Group suggests that

intracel-IV iron not be administered when patients have an activesystemic infection Clinical judgment is necessary in eachindividual patient to assess whether there is an immediateneed for IV iron (as opposed to delaying treatment untilresolution of an infection), likelihood of achieving benefitfrom a dose of IV iron in the setting of an active infection,and the severity of an infection

RESEARCH RECOMMENDATIONS

Much regarding the testing of iron status and use of ironsupplementation, particularly IV, in CKD patients of allstages remains unknown There is a serious lack of large,prospective clinical trials with assessment of clinically mean-ingful outcomes and toxicities; rather, most have been small,short-term studies focusing primarily on surrogate outcomessuch as increase in Hb level and reduction in ESA dose Some

c h a p t e r 2

important questions that should be addressed in future

studies might include:

K What is the comparative risk-benefit balance of various

treatment strategies that include differing ratios of ESA

dosing and iron supplementation to achieve a particular

Hb level?

K Is there a role, and if so under what circumstances, for

anemia management in CKD patients with iron alone,

without ESA treatment (or with only ESA ‘rescue

therapy’ for particularly low Hb levels)?

K Is there important long-term toxicity of IV iron

supplementation and if so, under what circumstances

and in what CKD patient groups?

K Is IV iron administration, with or without concomitant

ESA dose increases, safe and of clinical benefit, in patients

with ferritin levels 4500–800 ng/ml (4500–800 mg/l)?

K What are the best laboratory tests to guide decisions

regarding initiation, ongoing treatment, and

discontinua-tion of iron supplementadiscontinua-tion?

K Is current iron and anemia management in pediatric

CKD patients appropriate?

DISCLAIMER

While every effort is made by the publishers, editorial board,

and ISN to see that no inaccurate or misleading data, opinion

or statement appears in this Journal, they wish to make it

clear that the data and opinions appearing in the articles andadvertisements herein are the responsibility of the contri-butor, copyright holder, or advertiser concerned Accord-ingly, the publishers and the ISN, the editorial board andtheir respective employers, office and agents accept noliability whatsoever for the consequences of any suchinaccurate or misleading data, opinion or statement Whileevery effort is made to ensure that drug doses and otherquantities are presented accurately, readers are advised thatnew methods and techniques involving drug usage, anddescribed within this Journal, should only be followed inconjunction with the drug manufacturer’s own publishedliterature

SUPPLEMENTARY MATERIAL

Supplemental Table 2: Summary table of RCT examining the effect

of IV iron þ EPO vs EPO only in patients with HD-CKD (categorical outcomes).

Supplemental Table 3: Summary table of RCT examining the effect

of IV iron þ EPO vs EPO only in patients with HD-CKD (continuous outcomes).

Supplemental Table 4: Summary table of adverse events in RCT examining the effect of IV iron þ EPO vs EPO only in patients with HD-CKD (continuous outcomes).

Supplemental Table 5: Association between cumulative iron dose and clinical outcome in multivariable analyses.

Supplemental Table 6: Association between iron status and clinical outcome in multivariable analyses.

Supplementary material is linked to the online version of the paper at http://www.kdigo.org/clinical_practice_guidelines/anemia.php

c h a p t e r 2

Chapter 3: Use of ESAs and other agents* to treat anemia in CKD

Kidney International Supplements (2012) 2, 299–310; doi:10.1038/kisup.2012.35

ESA INITIATION

BACKGROUND

The introduction of recombinant human erythropoietin

(rHuEPO) into clinical practice in the 1980 s was a major

breakthrough in the treatment of the anemia of patients with

CKD The development of rHuEPO was aimed at replacing

the insufficient endogenous erythropoietin (EPO)

produc-tion related to CKD progression It remains unclear whether

the main cause of anemia is a loss of kidney EPO production

capacity or a derangement in oxygen sensing, as proposed

more recently.105

In the early years, rHuEPO administration was regarded

by the nephrology community as a beneficial therapy for

long-term dialysis patients whose Hb values fell to extremely

low levels, making them transfusion-dependent The

im-mediate benefit of rHuEPO in CKD patients with severe

anemia and anemia-related signs and symptoms was clear In

addition, the reduction in the need for regular blood

transfusions was another major benefit, resulting in

less frequent transmission of blood-borne viral diseases,

such as hepatitis B and C, less allosensitization, predisposing

to prolonged wait times or failure to receive a kidney

transplant, transplant rejection, and less transfusional

hemosiderosis.106–109

After introduction of rHuEPO into clinical practice its

administration was limited to dialysis patients with the most

severe forms of anemia Progressively, its use was extended to

the majority of dialysis patients with renal anemia, and

subsequently also to anemic patients with CKD 4–5 in

countries in which the high cost of rHuEPO did not limit the

number of patients eligible for this treatment

Hb targets also increased progressively, often into the

range of normal values The idea that anemia should be

corrected completely was based on pathophysiologic

con-siderations and the demonstration by numerous

observa-tional studies of an inverse association between Hb

concentrations up into the normal range and intermediate

outcomes such as left ventricular hypertrophy,110 as well as

hard patient outcomes such as cardiovascular events,111–113

hospital admission,114 and death.115,116 Of note, a recent

study also showed that CKD 5D patients with naturally

occurring Hb concentrations greater than 12 g/dl (120 g/l)

were not at increased mortality risk.117 However, the

suggestion drawn from epidemiological studies that anemia

should be completely corrected in patients with CKD was notsupported by the Normal Hematocrit Study in CKD 5Dpatients118 and several recent randomized controlled trials(RCTs) performed in large CKD patient cohorts (Supple-mentary Table 7 online)

In CKD 5D patients Hb concentrations often fall below

8 g/dl (80 g/l) if anemia is untreated, whereas in CKD NDpatients higher Hb concentrations are usual, unless patientsare close to dialysis or have another contributing cause Thedecision to prescribe ESAs should be based on evidenceaccrued from RCTs However substantial heterogeneity exists

in RCTs performed to evaluate ESA therapy, particularly inrelation to classification of patients, research design, baseline

Hb, target Hb, clinical outcome measures, and definitions ofclinically meaningful improvements

Outcomes of interest in RCTs of ESAs include mortality,cardiovascular and kidney endpoints, safety, quality of life(QoL), blood transfusions and cost QoL outcomes areparticularly important for CKD 5D patients and for somemay be more important than cardiovascular events ormortality, since they have relatively short life expectancyand the symptoms attributable to anemia (e.g., low energy,fatigue, decreased physical function, and low exercisecapacity) occur frequently and can be disabling.119However,QoL is extremely difficult to quantify as is the clinicalimportance of changes measured Furthermore, unlessassessed under rigorous double-blind conditions, the validity

of QoL measurements is questionable Avoidance of sions is important, as mentioned above

transfu-The guidelines to treat or not to treat the anemia of CKDare also valid for CKD 4–5T patients Of note, bloodtransfusions may increase the risk of alloreactivity andrejection episodes after kidney transplantation.120In addition

a recent randomized trial has shown that early post-kidneytransplant anemia correction by ESAs reduces the progres-sion of allograft nephropathy, although its effect on hardoutcomes in this patient population remains unknown.121

3.1: Address all correctable causes of anemia (includingiron deficiency and inflammatory states) prior toinitiation of ESA therapy (Not Graded)

RATIONALE

After diagnosing anemia in a patient with CKD all correctablecauses should be treated before considering ESA therapy.Above all, this recommendation is based on the observationthat iron supplementation given to CKD patients with

http://www.kidney-international.org c h a p t e r 3

& 2012 KDIGO

*Excluding iron which is discussed in Chapter 2.

proven iron deficiency or impaired iron availability

(‘func-tional iron deficiency’) generally leads to an increase in Hb

(See Chapter 2) However, the correction of other deficiency

states also may ameliorate anemia In patients with

inflammatory diseases, including bacterial and viral

infec-tions, the attenuation of the inflammatory status is often

followed by an improvement of Hb

There are several reasons why correctable causes other

than erythropoietin deficiency should be actively sought As

in any disease state, pathological conditions which can be

cured should be corrected first As examples, ESA treatment

is unlikely to be fully effective in raising Hb concentrations

until either severe systemic bacterial infections or severe

secondary hyperparathyroidism are appropriately treated

(Supplementary Table 8 online) When several different

factors are thought to contribute to the anemia of CKD, even

though the main underlying cause is impaired kidney EPO

synthesis, appropriate medical care dictates treating all

underlying causes

3.2: In initiating and maintaining ESA therapy, we

recommend balancing the potential benefits of

redu-cing blood transfusions and anemia-related symptoms

against the risks of harm in individual patients (e.g.,

stroke, vascular access loss, hypertension) (1B)

RATIONALE

Treatment of severe anemia

Objective evidence to support treatment of Hb

concentra-tions below 9 g/dl (90 g/l) is quite strong because the

transfusion benefits are substantial and the QoL

improve-ments are clinically important However the safety of ESAs in

treating severe anemia has not been evaluated in large

placebo controlled trials

The Canadian Erythropoietin Study Group reported

a double-blind RCT of 118 CKD 5HD patients in 1990

ESA was utilized in patients with Hb concentrationso9 g/dl

(o90 g/l), and three randomly allocated groups were

followed (placebo, target Hb 9.5–11 g/dl [95–110 g/l], high

target Hb 411 g/dl [4110 g/l]).122Baseline Hb was 7.0 g/dl

(70 g/l) and the mean transfusion requirement was 7

transfusions per year After 8 weeks, 58% (N¼ 23/40) in

the placebo group were transfused and only 2.5% (N¼ 1/40)

was transfused in the group with target Hb of 9.5–11g/dl

(95–110 g/l) and 2.6% (N¼ 1/38) in the group with target

Hb411g/dl (4110 g/l) After 6 months, significant

improve-ments in fatigue, physical function, and 6 minute walking

tests were reported for the low Hb group compared to

placebo, but no improvement was observed comparing low vs

high Hb group In an open-label RCT of only 83 CKD ND

patients with Hb o10 g/dl (o100 g/l), significant

improve-ments in energy and physical function were also reported.123

Treatment of moderate anemia

There are several large RCTs of ESA therapy where baseline

Hb is 410 g/dl (4100 g/l).118,124–128The intervention being

tested in these trials is complete correction of anemia withESAs, compared to partial correction with ESAs in fiveRCTs118,124–126,128 and to placebo in one.127 A double-blinddesign is necessary to accurately assess subjective or clinician-driven endpoints particularly QoL, starting dialysis, andgiving transfusions Notably, only 3 of the 6 trials weredouble-blind – the Normal Hematocrit Study reported in

1998,118 the Canada-Europe Study reported in 2005,126 andTREAT reported in 2009.127 The Scandinavian Study,125CREATE124and CHOIR128 trials were open label

The US Normal Hematocrit Trial by Besarab et al.118wasthe first of a series of RCTs which cast serious doubt on theassumption that full anemia correction should be achieved inthe majority of dialysis patients A cohort of 1233 prevalentCKD 5HD patients with symptomatic heart failure orischemic heart disease were allocated to either partialtreatment of anemia or full anemia correction, usingepoetin-alfa The eventually achieved hematocrit values were31% and 40%, respectively In the normal hematocrit grouptreated with epoetin there were 183 deaths and 19 myocardialinfarcts, producing 202 primary events, compared to 164events (150 deaths, 14 myocardial infarcts) in the group inwhich anemia was partially corrected with epoetin The riskratio for the primary endpoint was 1.3 (95% CI 0.9–1.9)which did not satisfy the pre-specified criterion for statisticalsignificance (even though the nominal p value was 0.03) afteradjusting for interim analyses The trial was stopped early in

a situation where the primary hypothesis was unlikely to beproven and the intervention being tested caused harm: 39%had vascular access clotting in the intervention arm and 29%

in the control arm (P¼ 0.001)

The double-blind Canada-Europe trial by Parfrey et al.126

of 596 incident CKD 5HD patients without symptomaticheart disease (18% with diabetic nephropathy) examined thequestion whether full anemia correction by epoetin-alfa inthe group randomized to a Hb target of 13.5–14.5 g/dl(135–145 g/l), as compared to partial treatment of anemia inthe group randomized to a Hb target of 9.5–11.5 g/dl(95–115 g/l), had a beneficial effect on left ventricular volumeand mass index The eventually achieved Hb values were 13.1and 10.8 g/dl (131 and 108 g/l), respectively There was nodifference in left ventricular volume index or mass indexbetween the two groups during this 96-week study Of note,patients in the full anemia correction group had asignificantly higher stroke incidence (secondary endpoint)than patients in the partial treatment correction group.However, the absolute numbers of patients with stroke werevery small As one might expect, the high Hb group receivedsignificantly fewer transfusions than the low Hb group, butextent of the benefit was modest: although 9% in the high Hbarm received at least one transfusion compared to 19% in thelow Hb arm (P¼ 0.004) during the 96-week study, thetransfusions per patient per year was 0.3 in the high Hb armand 0.7 in the low Hb arm (Po0.0001).129

In additionsignificant improvements in QoL were reported for the

a priori selected domains of vitality and of fatigue.126,130

c h a p t e r 3

The goal of the CREATE study by Drueke et al.124was to

show superiority of full anemia correction in terms of

cardiovascular events, as compared to partial correction of

anemia, when starting ESA therapy at an earlier stage than

end-stage renal disease (ESRD) In this trial, 603 CKD 3–5

patients (26% with diabetes) were randomly allocated to

either a Hb target of 13.0–15.0 g/dl (130–150 g/l) or a Hb

target of 10.5–11.5 g/dl (105–115 g/l) using epoetin-beta The

eventually achieved Hb values were 13.5 and 11.6 g/dl (135

and 116 g/l), respectively Dialysis was required in

signifi-cantly more patients in the high Hb group than in the low Hb

group However the rate of fall of GFR in the two groups

during the 3 year study was similar Statistically significant

improvements in some domains of QoL, including physical

function and vitality, were observed in the high Hb group,

although these must be interpreted cautiously because the

study was open-label

The US CHOIR study by Singh et al.128similarly aimed to

show superiority of full anemia correction by ESA

admin-istration in terms of cardiovascular events and death,

as compared to partial treatment of anemia, in patients

with CKD not yet on dialysis In this trial, 1432 CKD 3–4

patients (49% with diabetes) were randomized to Hb targets

of 13.5 g/dl (135 g/l) and 11.3 g/dl (113 g/l) using

epoetin-alfa Withdrawal rate was high: 17% due to renal replacement

therapy and 21% for other reasons The study was

prematurely stopped after an interim analysis with a median

study duration of 16 months The achieved Hb values

were 12.6 and 11.3 g/dl (126 and 113 g/l), respectively At this

time point, 125 patients in the complete anemia correction

group but only 97 patients in the standard correction

group had reached the primary combined cardiovascular

endpoint (P¼ 0.03) No differences in QoL were observed

comparing the two groups although, again, this finding must

be interpreted cautiously because the study was open-label

Finally, the international trial of darbepoetin-alfa in type 2

diabetes and CKD (TREAT) by Pfeffer et al.127 examined

cardiovascular and kidney outcomes in 4038 CKD 3–4

patients Of note, this is by far the largest ESA trial, and

has the best research design, as it was placebo controlled and

double-blinded Patients received either darbepoetin-alfa to

achieve a Hb target of 13.0 g/dl (130 g/l) or placebo with

rescue darbepoetin-alfa when the Hb concentration was

o9.0 g/dl (o90 g/l) The achieved Hb values were 12.5 and

10.6 g/dl (125 and 106 g/l), respectively The median

follow-up duration of the study was 29 months There were no

differences in the two primary endpoints, which were the

composite outcomes of death or a cardiovascular event (first

primary endpoint) and death or ESRD (second primary

endpoint) The hazard ratio for death/composite

cardiovas-cular event was 1.05 (95% CI 0.94–1.17), and for death or

ESRD it was 1.06 (95% CI 0.96–1.19) However there was a

substantial increased risk of stroke (HR 1.92; 95% CI

1.38–2.68), although the absolute risk of stroke overall was

modest: 5.0% of the high Hb group had a stroke compared to

2.6% in the placebo group (Po0.001) The relative increase

in risk of stroke was similar in patients with and without apast history of stroke As a result, the absolute risk of strokewas substantial in the 11% of subjects with a prior history ofstroke; 12% in the darbepoetin group compared to 4% in theplacebo group Venous thrombo-embolic events occurredsignificantly more frequently in the high Hb arm (2.0%)compared to the placebo arm (1.1%, P¼ 0.02) A signal thatnormalization of Hb with darbepoetin may be harmful inpatients with a history of malignancy was reported following

a post-hoc analysis: 14/188 (7.4%) of those with a history ofmalignancy at baseline died from cancer in the darbepoetinarm compared to 1/160 (0.6%) (P¼ 0.002) in the placeboarm A statistically significant improvement in FunctionalAssessment of Cancer Therapy-Fatigue (FACT-fatigue) scoreswas reported at week 26 favoring the darbepoetin group, butthe clinical significance of this was modest, as 55% of thehigh Hb group had a clinically important improvement infatigue score compared to 50% of the placebo group.Transfusions were prescribed relatively frequently, and moreoften in the placebo arm (25%) compared to the high Hbarm (15%) The harm:benefit trade-off in TREAT was 1stroke for 5 transfusions prevented by the high Hb target131(Supplementary Tables 9–19 online) In a large subset of theTREAT patients QoL was assessed using FACT-fatigue, SF-36,and EQ-5D through 97 weeks Compared to placebo,darbepoetin conferred a consistent, but small improvementover 97 weeks in fatigue and overall QoL, but none in energyand physical function Interim stroke had a substantialnegative impact on fatigue and physical function.132

Meta-analysesAssessment of ESAs in CKD using meta-analysis is proble-matic because of the heterogeneity of patients entered, thedifferent quality and research designs of the RCTs performed,and differences in definitions of endpoints In additionabstraction of aggregate data from the reports of RCTs topopulate the meta-analysis data base is also a limitation, asindividual patient data would be preferable The most recentmeta-analysis133concluded that higher Hb concentrations inCKD increases risk for stroke (relative risk [RR] 1.51, 95% CI1.03–2.21), hypertension (RR 1.67, 95% CI 1.31–2.12), andvascular access thrombosis (RR 1.33; 95% CI 1.16–1.53), andmay perhaps increase risk for death (RR 1.09; 95% CI0.99–1.20), serious cardiovascular events (RR 1.15, 95% CI0.98–1.33) or ESRD (RR 1.08; 95% CI 0.97–1.20) In ouropinion, because of the heterogeneity of patients andinterventions across studies in the meta-analysis greatercredence should be given to the results of the very large,placebo controlled, double-blind trial, TREAT, than to themeta-analyses, in areas where the results differ: TREAT found

no difference between the higher Hb, darbepoetin, group andthe lower Hb, placebo, group for the two primary compositeoutcomes (either death or a cardiovascular event, or death or

a renal event).127The existing meta-analyses of QoL outcomes are furthercomplicated by inclusion of data from open label studies,

c h a p t e r 3

different instruments to measure QoL, differences in research

design across RCTs, incomplete reporting as some trials chose

(a priori) specific domains as trial outcomes, and differences

in the definition of clinically meaningful improvement in

QoL domains.119 Results from two systematic reviews

published recently134,135 suggest that improvements in QoL

are maximized in the 10–12 g/dl (100–120 g/l) range In CKD

ND patients the review focused on energy and physical

function134 and in CKD 5D patients the review focused

on physical function and the meta-analysis on exercise

tolerance.135

3.3: We recommend using ESA therapy with great caution,

if at all, in CKD patients with active malignancy—in

particular when cure is the anticipated outcome—

(1B), a history of stroke (1B), or a history of

malignancy (2C)

RATIONALE

The joint guideline from the American Society of Clinical

Oncology136 and the American Society of Hematology137

recommend using ESA therapy with great caution in patients

with active malignancy, particularly when cure is the

anticipated outcome This advice is supported in CKD

patients by the post-hoc analysis in TREAT which

demon-strated a significantly higher death rate from cancer

in the darbepoetin arm in patients with a history of a

malignant condition at baseline as compared with the

placebo arm.127

The relative risk of stroke in patients in the darbepoetin

arm of TREAT was the same in those with and without a

history of stroke (i.e., approximately doubled) However

the absolute risk of stroke was much higher in subjects

with a history of stroke (in both study arms) and the absolute

risk of stroke attributable to high Hb/darbepoetin was

particularly high, 8% in those with a history of stroke vs

1% in those without a history of stroke over 29 months.138

Consequently the Work Group concluded that ESAs should

be used with great caution in those with a prior history

of stroke

3.4.1: For adult CKD ND patients with Hb concentration

Z10.0 g/dl (Z100 g/l), we suggest that ESA therapy

not be initiated (2D)

3.4.2: For adult CKD ND patients with Hb concentration

o10.0 g/dl (o100 g/l) we suggest that the decision

whether to initiate ESA therapy be individualized

based on the rate of fall of Hb concentration, prior

response to iron therapy, the risk of needing a

transfusion, the risks related to ESA therapy and the

presence of symptoms attributable to anemia (2C)

3.4.3: For adult CKD 5D patients, we suggest that ESA

therapy be used to avoid having the Hb

concentra-tion fall below 9.0 g/dl (90 g/l) by starting ESA

therapy when the hemoglobin is between 9.0–10.0 g/

dl (90–100 g/l) (2B)

3.4.4: Individualization of therapy is reasonable as somepatients may have improvements in quality of life athigher Hb concentration and ESA therapy may bestarted above 10.0 g/dl (100 g/l) (Not Graded)3.4.5: For all pediatric CKD patients, we suggest that theselection of Hb concentration at which ESA therapy

is initiated in the individual patient includesconsideration of potential benefits (e.g., improve-ment in quality of life, school attendance/perfor-mance, and avoidance of transfusion) and potentialharms (2D)

RATIONALE

In adult CKD-ND patients TREAT demonstrated that thehigh Hb darbepoetin arm was associated with harm In thepatients on placebo with rescue treatment allowed when Hbfell to below 9.0 g/dl (90 g/l) the achieved median Hb valuewas as high as 10.6 g/dl (106 g/l), despite the majority ofpatients receiving no or little darbepoetin127(SupplementaryTables 15–19 online)

There is no convincing evidence that the active increase of

Hb towards concentrations in the normal range leads todemonstrable benefit in adult patients with CKD stages 3–5.Moreover, when Hb falls below 10 g/dl (100 g/l) in thesepatients the Work Group were unconvinced that all patientsshould have an ESA initiated, particularly as the rate of Hbfall may be slow It was suggested that the decision to initiateESA therapy in CKD-ND when Hb is 49.0 ando10.0 g/dl(490 ando100 g/l) should be individualized based on risk

of requiring transfusions and on the presence of symptomsattributable to anemia, particularly as some patients may be

at higher risk of requiring red-cell transfusions, and somepatients are more prone to developing symptoms and signsassociated with anemia (Supplementary Tables 15–19 online)

In adult hemodialysis patients the rate of fall of Hb isfaster than in ND patients, and if untreated Hb willfrequently fall below 8 g/dl (80 g/l).122 As the risk oftransfusions is high in those HD patients whose Hb fallsbelow 9 g/dl (90 g/l) the Work Group suggested that ESAtherapy should be used to prevent the Hb concentration fromfalling below 9.0 g/dl (90 g/l), which in practice means thatthe Hb concentration at which ESA should be initiatedshould be between 9.0 and 10.0 g/dl [90 and 100 g/l] (Supple-mentary Tables 9–14 online)

However, there may be subgroups of adult CKD stage 3–5and 5D patients in whom it may not be wise to let Hb valuesdescend below 10 g/dl (100 g/l), particularly in elderlypatients who are more prone to developing symptoms andsigns associated with anemia, and those who are prone torequiring red-cell transfusions

Moreover, physical and mental performances and QoLmay be seriously compromised in adult CKD patients withsevere anemia RCTs supporting registration of epoetin-alfafor the treatment of anemia in dialysis patients demonstratedthat ESA treatment of subjects with a Hb of o 10 g/dl(o100 g/l) to a Hb target of approximately 10–12 g/dl

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(100–120 g/l) improved patient-reported physical

function-ing.134,135The question of the Hb value above which there is

no further improvement in these parameters remains

unsolved, especially for CKD-ND patients without diabetes

and CKD-5D patients with or without diabetes

In anemic children with CKD there are no RCTs examining

the effects of ESA administration on hard outcomes Therefore,

any suggestion for Hb targets in this subgroup of CKD patients

has to rely on results obtained in the adult CKD patient

population and on clinical experience in the pediatric setting

The upper and lower Hb targets are opinion-based, in keeping

with the lack of pediatric specific evidence There are a number

of factors unique to children that make exclusive reliance on

evidence in adults inappropriate such as age-specific variation of

normal Hb concentrations as well as QoL, growth,

develop-mental, and psychological differences between children and

adults.58Limited data suggest that children with CKD and a Hb

less than 9.9 g/dl (99 g/l) are at increased risk for mortality,139

left ventricular hypertrophy,140,141 and/or decreased exercise

capacity142compared to those with a Hb greater than 9.9 g/dl

(99 g/l) When evaluated as a continuous variable, hematocrit

(Hct) was linked directly to measures of improved health and

physical functioning in a health based QoL questionnaire

administered to a pediatric CKD population.143

ESA MAINTENANCE THERAPY

3.5.1: In general, we suggest that ESAs not be used to

maintain Hb concentration above 11.5 g/dl (115 g/l)

in adult patients with CKD (2C)

3.5.2: Individualization of therapy will be necessary as

some patients may have improvements in quality of

life at Hb concentration above 11.5 g/dl (115 g/l) and

will be prepared to accept the risks (Not Graded)

RATIONALE

The suggestion to set the upper Hb target in general to values

r11.5 g/dl (r115 g/l) in adult CKD patients is based on the

interpretation of the combined results of the recent major

RCTs that there may be more harm than benefit at higher Hb

concentrations Of note, the update of the 2006 KDOQI

anemia guideline in 2007 had already led to the

recommen-dation to limit the upper Hb target to 12 g/dl (120 g/l), not to

exceed 13 g/dl (130 g/l).51 The present suggestion not to

exceed in general a Hb limit of 11.5 g/dl (115 g/l) has been

influenced by the fact that the upper boundary of the Hb

concentration in the control group of the major ESA RCTs

usually did not exceed 11.5 g/dl (115 g/l); no data exist on the

benefits of Hb targets between 11.5 and 13.0 g/dl (115 and

130 g/l); and high Hb targets are associated with adverse

outcomes

The Work Group recognized that some patients

experi-ence an improvement in QoL when the Hb value is above

11.5 g/dl (115 g/l) This opinion is supported by the

heterogeneity of QoL outcomes in the major RCTs: in the

double-blind Canada-Europe Study and in open label

CREATE study statistically significant improvements in someQoL domains that may be clinically important were reportedwith higher Hb values.124,126,130In the double-blind TREATstudy the QoL benefits of higher Hb were modest127,132and

in open label CHOIR study no benefits were observed128(Supplementary Tables 9–19 online)

As all CKD patients in TREAT study also had type 2diabetes, it is possible that improvements in QoL may bemore difficult to achieve in this subgroup of patients than inthose not suffering from diabetes

An increase of Hb above 11.5 g/dl (115 g/l) towards 13 g/dl(130 g/l) may also be justified in individual patients with ahigh bleeding tendency since this results in lower transfusionneeds, as shown by 8 RCTs.133

Obviously, increasing Hb above 11.5 g/dl (115 g/l) up to

13 g/dl (130 g/l) has to be weighed against the probability ofincreased harm This perspective needs to be clearlyexplained to each patient who wishes to examine the possiblebenefits of more complete anemia correction

3.6: In all adult patients, we recommend that ESAs not beused to intentionally increase the Hb concentrationabove 13 g/dl (130 g/l) (1A)

RATIONALE

The strong recommendation not to aim for Hb increases toconcentrations 413 g/dl (4130 g/l) is based on the inter-pretation of the combined results of the recent major RCTsshowing more harm than benefit with higher Hb targets, ascompared to lower Hb targets, including increased risks forstroke,126,127hypertension,133and vascular access thrombosis(in hemodialysis patients).118 TREAT did not demonstratesignificant differences for serious cardiovascular or kidneyevents comparing correction of anemia with darbepoetin tothe placebo group.127Thus the increased risk of kidney eventsreported in CREATE124and of cardiovascular events reported

in CHOIR128 were not substantiated in the much largerTREAT trial.127 However, a recent meta-analysis pointestimate indicated increased mortality at higher Hb target133(Supplementary Tables 9–19 online)

An exception to the recommendation to avoid Hbincreases to concentrations 413 g/dl (4130 g/l) mighthowever be made for patients with comorbidities that arenormally associated with elevated Hb levels (e.g., cyanoticheart disease)

3.7: In all pediatric CKD patients receiving ESA therapy,

we suggest that the selected Hb concentration be inthe range of 11.0 to 12.0 g/dl (110 to 120 g/l) (2D)

RATIONALE

As mentioned above, in children with CKD observationaldata associates high Hb with better survival139 and/orincreased exercise capacity.142 Moreover, a recent NorthAmerican Pediatric Renal Trials and Collaborative Studies(NAPRTCS) retrospective analysis done on pediatric CKD

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